Drug Interactions between amoxicillin / clarithromycin / omeprazole and entrectinib

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of entrectinib, which is primarily metabolized by the isoenzyme. When a single 100 mg dose of entrectinib was administered with itraconazole, a potent CYP450 3A4 inhibitor, entrectinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 1.7- and 6-fold, respectively. Increased exposure to entrectinib may increase the risk and/or severity of adverse effects such as cognitive impairment, mood disorders, dizziness, sleep disturbances, liver enzyme elevations, hyperuricemia, congestive heart failure, edema, myocarditis, QT prolongation, vision problems, anemia, and neutropenia.

MANAGEMENT: Concomitant use of entrectinib with potent CYP450 3A4 inhibitors should be avoided when possible. If coadministration is necessary, the dosage of entrectinib should be reduced to 100 mg once daily for adults and pediatrics patients (12 years and older) with a body surface area (BSA) greater than 1.5 m2. Following discontinuation, and after an appropriate washout period of the CYP450 3A4 inhibitor (i.e., 3 to 5 half-lives), the entrectinib dosage taken prior to initiating the CYP450 3A4 inhibitor may be resumed. For pediatric patients with a body surface area of 1.5 m2 or less, concomitant use of entrectinib with potent CYP450 3A4 inhibitors should be avoided. Some authorities recommend if coadministration is unavoidable, adult patients should follow dose reduction guidance as described above while limiting coadministration to 14 days and do not recommend coadministration in pediatric patients (UK).

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.

Clarithromycin may increase and prolong the omeprazole plasma concentration. The mechanism may be related to clarithromycin inhibition of hepatic cytochrome P450 enzymes responsible for omeprazole metabolism. Coadministration of omeprazole may result in an increase in clarithromycin and 14-(R)-hydroxyclarithromycin plasma concentrations. These increases may be due to the effect of omeprazole on gastric pH.